Iron regulation and erythropoiesis

Current Opinion in Hematology

Volumn 15, Issue 3, 2008, Pages 169-175

  Nemeth, Elizabeta ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Anemia; Bone morphogenetic protein; Erythropoietic activity; Ferroportin; Hepcidin

Indexed keywords

BONE MORPHOGENETIC PROTEIN; BONE MORPHOGENETIC PROTEIN 2; BONE MORPHOGENETIC PROTEIN 4; FERROPORTIN; FLUROTHYL; HEMOJUVELIN; HEPCIDIN; IRON; TOLL LIKE RECEPTOR; TRANSFERRIN RECEPTOR 2;

ENZYME REGULATION; ERYTHROPOIESIS; HEMOCHROMATOSIS; HYPOXIA; INFLAMMATION; IRON BLOOD LEVEL; IRON METABOLISM; IRON STORAGE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN INTERACTION; REVIEW;

ANTIMICROBIAL CATIONIC PEPTIDES; BONE MORPHOGENETIC PROTEINS; CATION TRANSPORT PROTEINS; ERYTHROPOIESIS; HUMANS; IRON; IRON METABOLISM DISORDERS;

EID: 41949133287     PISSN: 10656251     EISSN: 15317048     Source Type: Journal    
DOI: 10.1097/MOH.0b013e3282f73335     Document Type: Review

References (59)

1. Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005; 1:191-200.
2. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001; 276:7806-7810.
3. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306:2090-2093.
4. Rivera S, Nemeth E, Gabayan V, et al. Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. Blood 2005; 106:2196-2199.
5. Nemeth E, Ganz T. Regulation of iron metabolism by hepcidin. Annu Rev Nutr 2006; 26:323-342. A comprehensive review of hepcidin regulation and its mechanism of action.
6. Xiao YT, Xiang LX, Shao JZ. Bone morphogenetic protein. Biochem Biophys Res Commun 2007; 362:550-553.
7. Wang RH, Li C, Xu X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2005; 2:399-409.
8. Truksa J, Peng H, Lee P, Beutler E. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of HFE, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl Acad Sci U S A 2006; 103:10289-10293.
9. Babitt JL, Huang FW, Xia Y, et al. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 2007; 117:1933-1939. Manipulation of the HJV/BMP pathway in vivo altered hepcidin and iron levels. Administration of BMP2 in mice increased hepcidin expression and administration of soluble HJV decreased hepcidin expression, with consequent changes in iron plasma levels and tissue distribution.
10. Xia Y, Sidis Y, Mukherjee A, et al. Localization and action of Dragon (repulsive guidance molecule b), a novel bone morphogenetic protein coreceptor, throughout the reproductive axis. Endocrinology 2005; 146:3614-3621.
11. Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006; 38:531-539. Hemojuvelin was shown to act as a coreceptor of the BMP pathway, directly binding to BMP2 and 4 and their receptors. Wild-type hemojuvelin, but not the hemojuvelin mutants, increased hepcidin expression by enhancing BMP signaling.
12. Lin L, Valore EV, Nemeth E, et al. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood 2007; 110:2182-2189. The first in-vitro model of hepcidin regulation by iron showed that hepatocytes sense iron-transferrin concentrations and increase hepcidin expression proportionally. The iron-regulatory pathway employs hemojuvelin and BMP2/4.
13. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004; 36:77-82.
14. Huang FW, Pinkus JL, Pinkus GS, et al. A mouse model of juvenile hemochromatosis. J Clin Invest 2005; 115:2187-2191.
15. Niederkofler V, Salie R, Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest 2005; 115:2180-2186.
16. Lin L, Goldberg YP, Ganz T. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood 2005; 106:2884-2889.
17. Zhang AS, West AP Jr, Wyman AE, et al. Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells. J Biol Chem 2005; 280:33885-33894.
18. Zhang AS, Anderson SA, Meyers KR, et al. Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. J Biol Chem 2007; 282:12547-12556. The first evidence that iron deficiency results in changes in soluble hemojuvelin levels in serum. The study also showed that neogenin participates in the generation of soluble hemojuvelin.
19. Lin L, Nemeth E, Goodnough JB, et al. Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site. Blood Cells Mol Dis 2007; 40:122-131.
20. Silvestri L, Pagani A, Camaschella C. Furin mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood 2007; 111:924-931. Soluble hemojuvelin was shown to be generated by furin cleavage and this can be increased by iron deficiency and hypoxia through the regulation of furin by HIF-1.
21. Kuninger D, Kuns-Hashimoto R, Kuzmickas R, Rotwein P. Complex biosynthesis of the muscle-enriched iron regulator RGMc. J Cell Sci 2006; 119:3273-3283.
22. Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem 2006; 281:28494-28498. HFE and TfR2 were shown to interact, and TfR2 competed with TfR1 for binding to HFE. The competition was maximal at high Fe-Tf levels, hinting at the likely mechanism for iron sensing in hepatocytes.
23. Schmidt PJ, Huang FW, Wrighting DM, et al. Hepcidin expression is regulated by a complex of hemochromatosis-associated proteins. ASH Annu Meeting Abstr 2006; 108:267.
24. Johnson MB, Enns CA. Diferric transferrin regulates transferrin receptor 2 protein stability. Blood 2004; 104:4287-4293.
25. Robb A, Wessling-Resnick M. Regulation of transferrin receptor 2 protein levels by transferrin. Blood 2004; 104:4294-4299.
26. Piperno A, Girelli D, Nemeth E, et al. Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis. Blood 2007; 110:4096-4100. HFE hemochromatosis patients failed to increase hepcidin in response to oral iron, both at diagnosis and after the patients were iron-depleted. The results indicate HFE is involved in hepcidin induction by acute iron changes.
27. Nemeth E, Roetto A, Garozzo G, et al. Hepcidin is decreased in TFR2 hemochromatosis. Blood 2005; 105:1803-1806.
28. Giannetti AM, Bjorkman PJ. HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface. J Biol Chem 2004; 279:25866-25875.
29. Johnson MB, Chen J, Murchison N, et al. Transferrin receptor 2: evidence for ligand-induced stabilization and redirection to a recycling pathway. Mol Biol Cell 2007; 18:743-754. The study described the mechanism of TfR2 stabilization by iron-transferrin.
30. Truksa J, Lee P, Peng H, et al. The distal location of the iron responsive region of the hepcidin promoter. Blood 2007; 110:3436-3437. The authors defined the regions of the hepcidin promoter necessary for the response to iron. Notably, the promoter study was carried out in vivo.
31. Truksa J, Peng H, Lee P, Beutler E. Different regulatory elements are required for response of hepcidin to interleukin-6 and bone morphogenetic proteins 4 and 9. Br J Haematol 2007; 139:138-147.
32. Milet J, Dehais V, Bourgain C, et al. Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance. Am J Hum Genet 2007; 81:799-807. The penetrance in HFE hemochromatosis was linked to certain polymorphisms in the BMP pathway, a known regulator of hepcidin expression.
33. Kearney SL, Nemeth E, Neufeld EJ, et al. Urinary hepcidin in congenital chronic anemias. Pediatr Blood Cancer 2007; 48:57-63.
34. Origa R, Galanello R, Ganz T, et al. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica 2007; 92:583-588. Thalassemia intermedia patients not requiring transfusions had similar liver iron concentrations as transfused thalassemia major patients, likely due to extreme hepcidin deficiency in thalassemia intermedia. Serum ferritin levels did not accurately reflect the relative liver iron load in the two conditions.
35. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002; 110:1037-1044.
36. Bondi A, Valentino P, Daraio F, et al. Hepatic expression of hemochromatosis genes in two mouse strains after phlebotomy and iron overload. Haematologica 2005; 90:1161-1167.
37. Pak M, Lopez MA, Gabayan V, et al. Suppression of hepcidin during anemia requires erythropoietic activity. Blood 2006; 108:3730-3735. Hepcidin suppression in anemia was determined by the erythropoietic activity and not by anemia per se, tissue hypoxia or direct EPO effects.
38. Vokurka M, Krijt J, Sulc K, Necas E. Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis. Physiol Res 2006; 55:667-674. Hepcidin suppression in anemia was related to the erythropoietic activity and iron utilization by the bone marrow.
39. Weizer-Stern O, Adamsky K, Amariglio N, et al. Downregulation of hepcidin and haemojuvelin expression in the hepatocyte cell-line HepG2 induced by thalassaemic sera. Br J Haematol 2006; 135:129-138. A serum factor in thalassemias had a suppressive effect on hepcidin expression in vitro.
40. Kemna EH, Kartikasari AE, van Tits LJ, et al. Regulation of hepcidin: insights from biochemical analyses on human serum samples. Blood Cells Mol Dis 2007; 16 Nov [Epub ahead of print].
41. Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007; 13:1096-1101. GDF-15 was identified as the bone marrow-derived factor that suppresses hepcidin in β-thalassemia.
42. Choi SO, Cho YS, Kim HL, Park JW. ROS mediate the hypoxic repression of the hepcidin gene by inhibiting C/EBPalpha and STAT-3. Biochem Biophys Res Commun 2007; 356:312-317. The study implicated ROS in hepcidin regulation.
43. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 2007; 117:1926-1932. HIF is directly involved in the regulation of hepcidin expression.
44. Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood 2006; 108:3204-3209. STAT3 was shown as the transcription factor used by IL-6 to regulate hepcidin.
45. Verga Falzacappa MV, Vujic SM, Kessler R, et al. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 2007; 109:353-358. STAT3 was shown as the transcription factor used by IL-6 to regulate hepcidin.
46. Pietrangelo A, Dierssen U, Valli L, et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology 2007; 132:294-300. STAT3 was shown as the transcription factor used by IL-6 to regulate hepcidin.
47. Rivera S, Gabayan V, Ganz T. In chronic inflammation, there exists an IL-6 independent pathway for the induction of hepcidin [abstract]. Blood 2004; 104:875a.
48. Lee P, Peng H, Gelbart T, et al. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci U S A 2005; 102:1906-1910.
49. Peyssonnaux C, Zinkernagel AS, Datta V, et al. TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood 2006; 107:3727-3732. Hepcidin production in macrophages was regulated in response to infection, suggesting an existence of a possible autocrine hepcidin effect on iron retention in macrophages during localized infection.
50. Liu XB, Nguyen NB, Marquess KD, et al. Regulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophages. Blood Cells Mol Dis 2005; 35:47-56.
51. Sow FB, Florence WC, Satoskar AR, et al. Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis. J Leukoc Biol 2007; 82:934-945.
52. Constante M, Wang D, Raymond VA, et al. Repression of repulsive guidance molecule C during inflammation is independent of Hfe and involves tumor necrosis factor-alpha. Am J Pathol 2007; 170:497-504. Hemojuvelin was shown to be suppressed by inflammation, suggesting a possible uncoupling of iron sensing from hepcidin regulation in inflammation.
53. Fujita N, Sugimoto R, Takeo M, et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med 2007; 13:97-104. Lower levels of hepcidin mRNA were seen in chronic hepatitis C patients, suggesting a possible mechanism for the development of iron overload in this disease.
54. Nicolas G, Viatte L, Lou DQ, et al. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet 2003; 34:97-101.
55. Viatte L, Nicolas G, Lou DQ, et al. Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice. Blood 2006; 107:2952-2958.
56. Roy CN, Andrews NC. Anemia of inflammation: the hepcidin link. Curr Opin Hematol 2005; 12:107-111.
57. Roy CN, Mak HH, Akpan I, et al. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood 2007; 109:4038-4044. Transgenic hepcidin overexpression in mice recapitulated the major features of anemia of inflammation in human patients.
58. Dallalio G, Law E, Means RT Jr. Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. Blood 2006; 107:2702-2704.
59. Kawabata H, Tomosugi N, Kanda J, et al. Antiinterleukin 6 receptor antibody tocilizumab reduces the level of serum hepcidin in patients with multicentric Castleman's disease. Haematologica 2007; 92:857-858. Anti-IL-6 therapy in Castleman's disease rapidly decreased hepcidin production and promtly improved anemia.